CN110835310A - Intermediate, preparation method and application - Google Patents

Intermediate, preparation method and application Download PDF

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CN110835310A
CN110835310A CN201910749281.3A CN201910749281A CN110835310A CN 110835310 A CN110835310 A CN 110835310A CN 201910749281 A CN201910749281 A CN 201910749281A CN 110835310 A CN110835310 A CN 110835310A
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protecting
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hydrogen
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李世红
何静
蔡飞
闫恒
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Neuboron Medtech Ltd
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Abstract

The invention provides an intermediate, a preparation method and application thereof. The intermediate can be used to obtain high purity18F-BPA, simplified in18The synthesis step after the F labeling is simple to operate and high in efficiency.

Description

Intermediate, preparation method and application
Technical Field
The invention belongs to the field of medicine and chemical synthesis, and particularly relates to an intermediate, a preparation method and application thereof.
Background
Malignant tumors are serious diseases that seriously endanger human health and life, and the treatment of malignant tumors is mainly performed by radiotherapy or chemotherapy at present. Boron Neutron Capture Therapy (BNCT) uses nuclear reactions that occur within tumor cells to destroy cancer cells. By using boron (B)10B) The medicine has the characteristic of high capture cross section for thermal neutrons10B(n,α)7Li neutron capture and nuclear fission reaction generation4He and7the average Energy of the two charged particles is about 2.33MeV, the two charged particles have high Linear Energy Transfer (LET) and short-range characteristics, the Linear Energy Transfer and the range of the α particles are 150 keV/mum and 8μm respectively7The Li heavily-charged particles are 175 keV/mum and 5μm, the total range of the two particles is about equal to the size of a cell, so the radiation damage to organisms can be limited at the cell level, when boron-containing drugs selectively gather in tumor cells, and a proper neutron source is matched, the aim of locally killing the tumor cells can be achieved on the premise of not causing too much damage to normal tissues. The effect of boron neutron capture therapy is also called binary radioactive cancer therapy (binaryancertherapy) because the effect depends on the boron-containing drug concentration and the quantity of thermal neutrons at the tumor cell position; it is known that, in addition to the development of neutron sources, the development of boron-containing drugs plays an important role in the research of boron neutron capture therapy. (10B) borono-L-phenylalanine (4-, (10B)borono-L-phenylalanine，L-10BPA) is a boron-containing drug used for BNCT to treat cancer, and has good curative effect on various malignant tumors, such as diseases of multi-linear glioblastoma (glioblastomas), melanoma (melanoma) and the like. BNCT treatment protocols are developed according to18Tumor targeting outcome guidance for F-BPA (2-fluoro-4-borono-L-phenylalanine) using positron-emitting radionuclides18F-labeled BPA is used in conjunction with Positron Emission Tomography (PET) to diagnose brain tumors and other types of solid tumors.
CN105916836A discloses a method for producing 2-fluoro-4-borono-L-phenylalanine and a precursor of 2-fluoro-4-borono-L-phenylalanine. Which is prepared by18F ion replaces leaving group on benzene ring to obtain18F-labeled halogen-substituted phenylalanine compound is obtained through coupling reaction18F-BPA. CN105348309B on the benzene Ring18F, reacting aldehyde group on benzene ring with phenyl oxazoline ketone to obtain18F-BPA. CN102887913B through18F ion replaces nitro on benzene ring to obtain18F-labeled iodine-substituted phenylalanine compound is obtained through coupling reaction18F-BPA. The above methods are all described in18And after the labeling, the substitution reaction of boric acid ester is carried out, so that the reaction steps are multiple, and the preparation time is long.
Due to the fact that18F half-life of about 110min, labeling18After F, how to simplify the preparation steps and shorten the preparation time is a significant and challenging research, which is related to the radiochemical yield and the application limit of the synthesis. Therefore, a simple and efficient preparation method which meets clinical requirements and has mild reaction conditions and high yield is developed18The use of F-BPA is of great importance.
Disclosure of Invention
The invention aims to provide an intermediate, a preparation method thereof and a method for preparing 2-fluoro-4-dihydroxy boron-phenylalanine (18F-BPA). The synthesis18The process of F-BPA is simplified in18F markThe subsequent synthesis steps are simple and efficient, the yield is high, the product purity is high, and the radiochemical yield of the synthesis is improved.
In a first aspect of the invention, there is provided an intermediate I having the structure:
wherein R is1、R2Is halogen or R1、R2Is a boronic acid group or a substituent hydrolysable to a boronic acid group;
R3and R4Each independently hydrogen or a protecting group for amino or together with amino forms an imino group for protecting amino;
R5is a protecting group for hydrogen or carboxyl.
Wherein said intermediate I comprises two configurations:
Figure BDA0002166641690000022
in another preferred embodiment, the intermediates include intermediate I-1 and intermediate I-2,
the intermediate I-1 has the structure:
the intermediate I-2 has the structure:
Figure BDA0002166641690000024
the compound I-2 comprises an L configurationAnd configuration D
Said X1、X2Is halogen, preferably, said X1、X2Is chlorine, bromine or iodine; b represents boron, preferably10Boron; r10And R20Is OH or together with the boron atom to which they are attached represents a substituent hydrolysable to a boronic acid group, preferably a boronic acid pinacol ester group; r3And R4Hydrogen, a protecting group for amino group, or an imino group which forms a protecting group for amino group together with amino group, respectively; r5Is a protecting group for hydrogen or carboxyl.
In another preferred embodiment, R is3、R4Examples of the amino-protecting group include an alkoxycarbonyl-based protecting group, an acyl-based protecting group, and an alkyl-based protecting group. Preferably, R3、R4The protecting group for amino group further includes a substituent selected from the group consisting of: benzyloxycarbonyl, tert-butoxycarbonyl, fluorenyl-methoxycarbonyl, allyloxycarbonyl, trimethylsilyloxycarbonyl, methyl (or ethyl) oxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, o- (p) -nitrobenzenesulfonyl, pivaloyl, benzoyl, trityl, 2, 4-dimethoxybenzyl, p-methoxybenzyl, benzyl.
In another preferred embodiment, R3And R4Together with N, the protecting group as an amino group forms a C ═ N bond; preferably, -NR3R4Is composed of
In another preferred embodiment, the substituent hydrolyzable to a boronic acid group is a boronic ester group. Boron in the present application is preferably boron10And boron.
In another preferred embodiment, the protecting group for carboxyl group includes: substituted or unsubstituted C1-20 alkyl. The substituent group comprises phenyl, halogen, nitro, hydroxyl and methoxyl. Preferably, the protecting group of the carboxyl is C1-10 alkyl, phenyl, benzyl. Preferably, the protecting group for carboxyl group includes: substituted or unsubstituted C1-C20 alkyl; the substituent group comprises phenyl, halogen, nitro, hydroxyl and methoxy; preferably C1-C10 alkyl, phenyl, benzyl. Preferably, the protecting group for carboxyl group further comprises: methyl, ethyl, isopropyl, tert-butyl, benzhydryl, benzyl, p-nitrobenzyl, p-methoxybenzyl, 4-pyridinebenzyl, trichloroethyl, methylthioethyl, p-toluenesulfonylethyl, p-nitrophenylthioethyl, phenyl, benzyl.
In another preferred embodiment, the intermediate I is selected from the following compounds:
Figure BDA0002166641690000041
in a second aspect of the invention, there is provided a process for the preparation of an intermediate as described in the first aspect of the invention, the process comprising:
ii) reaction of the intermediate I-1 with boric acid or a borate to give an intermediate I-2
Figure BDA0002166641690000042
Wherein the content of the first and second substances,
X1、X2is halogen, preferably, said X1、X2Is chlorine, bromine or iodine;
b represents boron, preferably10Boron;
R10and R20Is OH or together with the boron atom to which they are attached represents a substituent hydrolysable to a boronic acid group, preferably a boronic acid pinacol ester group;
R3and R4Hydrogen, a protecting group for amino group, or an imino group which forms a protecting group for amino group together with amino group, respectively;
R5is a protecting group for hydrogen or carboxyl.
In another preferred embodiment, the intermediate I-1 is reacted with boric acid or a borate under the protection of nitrogen.
In another preferred embodiment, the intermediate I-1 is reacted with a boronic acid or boronic ester at a temperature of from 20 ℃ to 100 ℃, preferably from 50 ℃ to 100 ℃.
The palladium catalyst is not particularly limited. Preferably, the palladium catalyst is selected from the group consisting of: tris (dibenzylideneacetone) dipalladium (Pd)2(dba)3) Tetrakis (triphenylphosphine) palladium (Pd (PPh)3)4) Palladium acetate, palladium chloride, dichlorobis (triphenylphosphine) palladium, palladium trifluoroacetate, triphenylphosphine palladium acetate, [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, bis (tri-o-phenylphosphino) palladium dichloride, 1, 2-bis (diphenylphosphino) ethane palladium dichloride, or a combination thereof.
The borate ester is not particularly limited. Preferably, the borate ester is selected from the group consisting of: pinacol diboron, catechol borate, bis (3, 3-dimethyl-2, 4-pentanediol) borate, triethanolamine borate, trimethyl borate, triisopropyl borate, triethyl borate, tributyl borate, neopentyl glycol diborate, or combinations thereof.
In another preferred embodiment, the halogen is chlorine, bromine or iodine.
In another preferred example, the method further comprises: i) the intermediate II reacts with the intermediate III to obtain an intermediate I-1
Wherein, X1、X2、X3Are each halogen; preferably, said X1、X2、X3Is iodine, or X1、X2、X3Is bromine; r3And R4Each independently hydrogen or a protecting group for amino or together with amino forms an imino group for protecting amino; r5Is a protecting group for hydrogen or carboxyl.
In another preferred embodiment, the intermediate III is
Figure BDA0002166641690000052
The intermediate I-1 is
Figure BDA0002166641690000053
Wherein, X1、X2Is halogen, preferably, said X1、X2Is chlorine, bromine or iodine; r5Is a protecting group for hydrogen or carboxyl.
In another preferred example, the method further comprises: hydrolyzing under acidic condition to deprotect amino group in said intermediate I-1, and Boc2Reacting O under alkaline condition, and protecting amino in the intermediate I-1 by Boc to obtain compound
Figure BDA0002166641690000054
Thereafter, with a boronic acid or boronic ester, preferably at room temperature, preferably R5Is C1-10 alkyl.
In another preferred example, the method further comprises: the intermediate I-1 is subjected to manual resolution to obtain a compound I-1a with an L configuration and a compound I-1b with a D configuration, and then the obtained products are respectively reacted with boric acid or boric acid ester
Figure BDA0002166641690000055
Figure BDA0002166641690000061
In a third aspect of the invention there is provided the use of an intermediate I as described in the first aspect of the invention for the preparation of18F-BPA, said18F-BPA has the structure:
in another preferred example, the method comprises: reacting intermediate I-2 with18F ion reaction to obtain18F-substituted compounds
Deprotection of the18Protecting groups in F-substituted compounds to give18F-BPA
In another preferred embodiment, the method comprises using Cu (OTf)2Py4Or Cu (OTf)2The step (2).
In another preferred embodiment, the method comprises using a solvent selected from the group consisting of: water, methanol, DMF, DMA, DMSO, acetonitrile, n-butanol, ethanol, dichloromethane, or a mixed solution of any combination thereof.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 is a hydrogen spectrum of tert-butyl N, N-bis (tert-butoxycarbonyl) -2, 4-bis (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -phenylalanine prepared in example 6;
FIG. 2 is a schematic representation of the present invention18F-BPA radioactive HPLC profile;
FIG. 3 is a schematic representation of the present invention18F-BPA and standard substance19Radioactivity HPLC pattern after mixing of F-BPA.
Detailed Description
The present inventors have made extensive and intensive studies to prepare a compound useful for the preparation of18An intermediate of F-BPA, said intermediate comprising a phenylalanine intermediate substituted with a pinacol ester bisboronic acid by substituting a pinacol ester boronic acid ester group ortho to an alanine group to18F, can obtain18F-BPA. The method is shortened in18Preparation after F labelling18The F-BPA step is simple and efficient, the yield is high, the product purity is high, and the radiochemical yield of the synthesis is improved. On the basis of this, the present invention has been completed.
Term(s) for
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter claimed. In this application, the use of the singular also includes the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the term "comprising" as well as other forms, such as "includes," "including," and "containing," are not limiting.
When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, -CH2O-is equivalent to-OCH2-。
The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.
In addition to the foregoing, the following terms, when used in the specification and claims of this application, have the meanings indicated below, unless otherwise specifically indicated.
In the present application, the term "halogen" refers to fluorine, chlorine, bromine, iodine. "F" refers to fluorine, including both radioactive and non-radioactive fluorine, e.g.18F、19F, preferably18F. "B" refers to boron, including boron having both radioactive and non-radioactive properties, preferably boron having both radioactive and non-radioactive properties10B. "N" refers to nitrogen. "nitro" means-NO2A group. "amino" means-NH2A group. "Borate" means-B (OH)2A group.
In the present application, the term "alkyl", as a group or as part of another group (for example as used in groups such as halogen-substituted alkyl), means a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, free of unsaturation, having, for example, from 1 to 10 carbon atoms, and attached to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, and the like. The term "C1-10 alkyl" refers to alkyl groups having 1-10 carbon atoms such as methyl, ethyl, propyl, isopropyl, pentyl, and the like.
Preferably, the inert solvent is selected from the group consisting of: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran dichloromethane, chloroform, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dioxane, or a combination thereof; more preferably, the inert solvent is a mixed solvent of benzene and water.
The term "substituent hydrolyzable to a boronic acid group" means that the substituent, upon hydrolysis, can form a boronic acid group (-B (OH)2) Such as a borate group, including but not limited to the following substituents:
Figure BDA0002166641690000081
Figure BDA0002166641690000082
the boronic acid pinacol ester group is preferred.
In the present invention, R3And R4The protecting groups for amino groups may be protecting groups, respectively, including but not limited to, alkoxycarbonyl-based protecting groups, acyl-based protecting groups, alkyl-based protecting groups; r3And R4The amino group may be protected by imine (C ═ N) with N, for example
Figure BDA0002166641690000083
Both of the above protecting group forms should be within the understanding of the "protecting group for amino" as described herein. Wherein, the alkoxycarbonyl protecting group includes but is not limited to: benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenyl methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylSilicon ethoxycarbonyl (Teoc) and methoxy (or ethoxy) oxycarbonyl. The acyl protecting groups include, but are not limited to: phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o- (p) -nitrobenzenesulfonyl (Ns), pivaloyl, benzoyl. The alkyl protecting groups include, but are not limited to: trityl (Trt), 2, 4-dimethoxybenzyl (Dmb), p-methoxybenzyl (PMB), benzyl (Bn).
The term "protecting group for a carboxyl group" refers to a protecting group that forms an ester group, amide, or hydrazide with a carboxyl group, including but not limited to alkyl, phenyl, alkyl-substituted amino. Among them, the "alkyl group" is preferably a linear or branched alkyl group substituted or unsubstituted with a substituent having 1 to 20 carbon atoms, such as methyl, ethyl, isopropyl, tert-butyl, benzhydryl, benzyl, p-nitrobenzyl, p-methoxybenzyl, 4-pyridinebenzyl, trichloroethyl, methylthioethyl, p-toluenesulfonylethyl, p-nitrophenylthioethyl, and the like.
In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.
The present invention is intended to cover various stereoisomers and mixtures thereof, by "stereoisomer" is meant a compound consisting of the same atoms, bonded by the same bonds, but having a different three-dimensional structure. All tautomeric forms of the compounds of the invention are intended to be included within the scope of the invention, a "tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule.
The intermediate compounds described herein contain chiral carbon atoms and, thus, may give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral carbon atom may be defined as (R) -or (S) -, based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the invention may be prepared by selecting as starting materials or intermediates racemates, diastereomers or enantiomers. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, e.g., crystallization and chiral chromatography. The intermediate has two configurations of an L-type phenylalanine structure and a D-type phenylalanine structure, and is within the protection scope of the invention.
18Process for the preparation of F-BPA
The invention relates to a new18The process for the preparation of F-BPA can be obtained, for example, by the following examples, but is not limited to the examples. The amino group, carboxyl group protecting group and borate group used in the following reaction formula may be appropriately modified and are not limited to the exemplified methods.
The method comprises the following steps: reacting intermediate I-2 with18F ion reaction to obtain18F-substituted compounds
Figure BDA0002166641690000091
Deprotection of the18Amino and/or carboxyl in F-substituted compounds, to obtain18F-BPA
Figure BDA0002166641690000092
The reaction temperature in the reaction of each step may be suitably selected depending on the solvent, starting material, reagent, etc., and the reaction time may be suitably selected depending on the reaction temperature, solvent, starting material, reagent, etc. After the reaction in each step, the target compound may be separated and purified from the reaction system by a conventional method, such as filtration, extraction, recrystallization, washing, silica gel column chromatography, etc. Under the condition of not influencing the next reaction, the target compound can also directly enter the next reaction without separation and purification.
In the intermediate I Synthesis18In the step of F-BPA, the catalyst used18F ion ([ 2 ]18F]F-) Bombardment H with proton beams may be used2 18O, by18O (p, n) is reacted or obtained using methods known in the art. Make it18Capturing F ion on ion exchange column with K2.2.2/K2CO3And eluting the mixed solution, and dehydrating and drying the eluted mixed solution for a labeling reaction. Reacting intermediate I-2 with18F ion reaction, purifying the mixed solution by a cation column, drying, hydrolyzing and removing the protecting groups of amino and carboxyl to obtain the product18F-BPA. The reagent used comprises hydrogen fluoride and potassium fluoride. The solvent used includes water, methanol, DMF, DMA, DMSO, acetonitrile, n-butanol, ethanol, dichloromethane, etc., or any mixed solvent thereof. The reaction temperature is preferably 20 to 150 ℃ and more preferably 100-130 ℃. The reaction time is preferably 5 minutes to 1 hour, more preferably 10 to 30 minutes. The water removal drying may remove water azeotropically by adding a dry organic solvent, which may be used include, but are not limited to: acetonitrile, Dimethylsulfoxide (DMSO), Dimethylformamide (DMF), Dimethylacetamide (DMA), or any combination thereof. In a preferred embodiment, the intermediates I are reacted with18The F ion reaction may incorporate a copper catalyst, which may be used including, but not limited to: cu (OTf)2Py4、Cu(OTf)2Or a combination thereof.
It is to be noted that the intermediates I of the present invention and18F-BPA includes all optical isomers thereof, including isomers having phenylalanine structure with L configuration and isomers having phenylalanine structure with D configuration. For example,18F-BPA comprising a phenylalanine structure having the L configuration18F-L-BPA or D configuration phenylalanine structure18F-D-BPA. In the preparation method, the intermediate I can be subjected to chiral resolution to obtain a compound with a single configuration to participate in the reaction, or can be directly subjected to the reaction without resolution to obtain the compound18F-BPA。
The present invention is further illustrated by the following examples. It is to be understood that the following description is only of the most preferred embodiments of the present invention and should not be taken as limiting the scope of the invention. In the following examples, the experimental methods without specific conditions, usually according to the conventional conditions or according to the conditions suggested by the manufacturers, can be modified by those skilled in the art without essential changes, and such modifications should be considered as included in the protection scope of the present invention. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
EXAMPLE 1 preparation of tert-butyl N-diphenylmethylene-2, 4-dibromophenylalanine
N-Diphenylmethylene-glycine tert-butyl ester (40g,135.42mmol,1eq), 1, 4-dibromobenzyl bromide (44.53g,135.42mmol,1eq), tetrabutylammonium bromide (TBAB,436.55mg,1.35mmol,0.01eq) were dissolved in 300mL of toluene, and 80mL of aqueous potassium hydroxide (100.00g,1.78mol,13.16eq) were added. The reaction was stirred at 25 ℃ for 12 hours to completion. The reaction mixture was diluted with 100mL of ethyl acetate, extracted with 400mL (200 mL. times.2) of ethyl acetate, the organic phases were combined and washed with 600mL (300 mL. times.2) of saturated brine, and washed with Na2SO4Drying and filtering to obtain a solid. The crude product was isolated by column chromatography (petroleum ether/ethyl acetate 100:1-20:1) to yield 15g of product.
LCMS:MS(M+H+)＝544.0
1HNMR:400MHz,CDCl3
δ7.56-7.46(m,3H),7.35-7.16(m,7H),7.01(d,J＝8.2Hz,1H),6.59(br d,J＝6.8Hz,2H),4.23(dd,J＝4.2,9.5Hz,1H),3.31(dd,J＝4.0,13.4Hz,1H),3.11(dd,J＝9.6,13.5Hz,1H),1.41-1.28(m,9H)。
Figure BDA0002166641690000111
EXAMPLE 2 preparation of tert-butyl N-Boc-2, 4-dibromophenylalanine
N-Diphenylmethylene-2, 4-dibromophenylalanine tert-butyl ester (30g,55.22mmol,1eq) is dissolved in THF (70mL), 20mL of an aqueous solution of citric acid (31.83g,165.66mmol,31.86mL,3eq) is added, and stirring is carried out at 25 ℃ for 12 h. Adding Na2CO350mL of an aqueous solution (29.26g,276.10mmol,5eq) and Boc2O(13.26g,60.74mmol,1395mL,1.1eq), stirring was continued for 4 h. After completion of the reaction, the reaction mixture was extracted with 400mL (200 mL. times.2) of ethyl acetate, the organic phases were mixed and washed with 400mL (200 mL. times.2) of saturated brine, Na2SO4Drying and filtering to obtain a solid. The crude product was isolated by column chromatography (100: 1-10:1 petroleum ether/ethyl acetate) to give 19.6g of product in 73.48% yield and 99.2% purity.
LCMS:MS(M-155+)＝323.9
1HNMR:400MHz,CDCl3
δ7.72(d,J＝1.5Hz,1H,7.37(dd,J＝1.8,8.1Hz,1H),7.13(br d,J＝8.1Hz,1H),5.06(br d,J＝8.3Hz,1H),4.59-4.38(m,1H),3.23(dd,J＝5.9,13.9Hz,1H),3.00(br dd,J＝8.6,13.8Hz,1H),1.40(br d,J＝16.6Hz,17H)。
Figure BDA0002166641690000112
EXAMPLE 3 chiral resolution of tert-butyl N-Boc-2, 4-dibromophenylalanine
19.6g of tert-butyl N-tert-butoxycarbonyl-2, 4-dibromophenylalanine were separated by SFC (column: DAICELCHIRALPAKAY (250 mm. times.50 mm,10 um); mobile phase: [ 0.1% NH ]3H2O MEOH]) 9.1g of product is obtained, the yield is 46.84 percent, and the purity is 97.8 percent; and 9.2g of product, 48.18% yield, 99.5% purity.
Figure BDA0002166641690000121
Example 4
Preparation of N-tert-Butoxycarbonyl-2, 4-bis (4,4,5, 5-tetramethyl-1, 3, 2-dioxaboron-2-yl) -phenylalanine tert-butyl ester
N-Boc-2, 4-dibromo-phenylalanine tert-butyl ester (7.50g,15.6mmol,1.00eq), pinacol diboron (19.8g,78.2mmol,5.00eq), KOAc (6.14g,62.6mmol,4.00eq), Pd (dppf) Cl2(1.15g,1.57mmol,0.10eq) and dioxane (75.0mL) were stirred at 90 ℃ under nitrogen for 1 h. After the reaction was complete, it was filtered, 200mL of water were added, and 300mL (100 mL. times.3) of ethyl acetate was used as the reaction mixtureExtraction with ethyl acetate, mixing of the organic phases, washing with 200mL (100 mL. times.2) of saturated brine, Na2SO4Drying and filtering to obtain a solid. The crude product was purified by HPLC to give 6.5g of product, 96.3% pure.
LCMS:MS(M+H+-156)＝418.0
1HNMR:400MHz,CDCl3
8.24(s,1H),7.84(d,J＝7.6,1H),7.30(d,J＝7.6,1H),5.90(d,J＝8.4,1H),4.24-4.19(m,1H),3.24-3.19(m,2H),1.47(s,9H),1.39(s,12H),1.34(s,12H),1.32(s,9H).
Figure BDA0002166641690000122
Example 5
Preparation of N-tert-Butoxycarbonyl-2, 4-bis (4,4,5, 5-tetramethyl-1, 3, 2-dioxaboron-2-yl) -phenylalanine tert-butyl ester
O-Boc-2, 4-dibromo-phenylalanine tert-butyl ester (7.00g,14.6mmol,1.00eq), pinacol diboride (18.5g,73.0mmol,5.00eq), KOAc (5.73g,58.4mmol,4.00eq), Pd (dppf) Cl2(5.73g,58.4mmol,4.00eq) and dioxane (70.0mL) were stirred at 90 ℃ under nitrogen for 3 h. After completion of the reaction, filtration was carried out, 200mL of water was added, the reaction mixture was extracted with 300mL (100 mL. times.3) of ethyl acetate, the organic phases were mixed and washed with 200mL (100 mL. times.2) of saturated brine, and Na2SO4Drying and filtering to obtain a solid. The crude product was purified by HPLC to give 5.37g of product, 97.35% pure.
LCMS:MS(M-100-55+H+):418.3
1HNMR:400MHz,CDCl3
δ1.31-1.35(m,21H),1.39(s,12H),1.47(s,9H),3.16-3.29(m,2H),4.19-4.26(m,1H),5.89(br d,J＝8.40Hz,1H),7.30(d,J＝8.00Hz,1H),7.84(dd,J＝7.60,1.47Hz,1H),8.24(s,1H)
Figure BDA0002166641690000131
Example 6
Preparation of N, N-di (tert-butyloxycarbonyl) -2, 4-di (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -phenylalanine tert-butyl ester
N-Boc-2, 4-dibromo-phenylalanine tert-butyl ester (7.00g,14.6mmol,1.00eq), pinacol diboron (18.5g,73.0mmol,5.00eq), KOAc (5.73g,58.4mmol,4.00eq), Pd (dppf) Cl2(5.73g,58.4mmol,4.00eq) and dioxane (70.0mL) were stirred at 90 ℃ under nitrogen for 3 h. After completion of the reaction, filtration was carried out, 200mL of water was added, the reaction mixture was extracted with 300mL (100 mL. times.3) of ethyl acetate, the organic phases were mixed and washed with 200mL (100 mL. times.2) of saturated brine, and Na2SO4Drying and filtering to obtain a solid. The crude product was purified by HPLC to give 5.37g of product, 97.35% pure. The hydrogen spectrum is shown in FIG. 1.
Figure BDA0002166641690000141
Example 7
Preparation of18F-BPA
To H2 18O irradiation of accelerated protons by18O (p, n) reaction to obtain18Capturing F ion in ion exchange column with K2.2.2/K2CO3And eluting the mixed solution, and dehydrating and drying the eluted mixed solution for a labeling reaction. The compound obtained in example 5 was reacted in DMA solution18F ion in Cu (OTf)2Py4Reacting for 15min in the presence, purifying the mixed solution by a cation column after the reaction is finished, and drying. Reacting in HCl solution at 110 deg.C for 10min, adding NaOH solution to neutralize, hydrolyzing to remove amino and carboxyl protecting groups to obtain crude product. Purifying the crude product by HPLC to obtain a product with a purity of greater than 99%18F-BPA。
The radioactive HPLC spectrum is shown in FIG. 2. Mixing the product with small amount of standard substance19F-BPA is mixed and injected into HPLC together, under the same condition, the peak appears at the position of retention time (retention time 11min +/-1 min), and the marked product is proved to be18F-BPA, see FIG. 3.
Figure BDA0002166641690000142
Preparation from the Compound obtained in example 6 by the same preparation method as described above18F-BPA, likewise with a purity of more than 99%18F-BPA。
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. An intermediate I, wherein said intermediate I has the structure
Figure FDA0002166641680000011
Wherein
R1、R2Is halogen or R1、R2Is a boronic acid group or a substituent hydrolysable to a boronic acid group;
R3、R4hydrogen, a protecting group for amino group, or an imino group which forms a protecting group for amino group together with amino group, respectively;
R5a protecting group which is hydrogen or a carboxyl group;
preferably, said intermediate I comprises two configurations thereof:
Figure FDA0002166641680000012
2. the intermediate I of claim 1, wherein intermediate I comprises intermediates I-1 and I-2, wherein intermediate I-1 has the structure:
Figure FDA0002166641680000013
the intermediate I-2 has the structure:
Figure FDA0002166641680000014
wherein the content of the first and second substances,
X1、X2is halogen;
b represents boron, preferably10Boron;
R10and R20Is OH or together with the boron atom to which they are attached represents a substituent hydrolysable to a boronic acid group;
R3and R4Hydrogen, a protecting group for amino group, or an imino group which forms a protecting group for amino group together with amino group, respectively;
R5is a protecting group for hydrogen or carboxyl.
3. The intermediate I according to claim 1 or 2, wherein the substituents hydrolysable to boronic acid groups are boronic ester groups, preferably boronic acid pinacol ester groups; r3And R4Comprises alkoxycarbonyl protecting groups, acyl protecting groups and alkyl protecting groups; r5Including substituted or unsubstituted C1-20 alkyl groups, preferably t-butyl.
4. The intermediate I according to any one of claims 1 to 3, wherein the intermediate I is selected from the following compounds:
Figure FDA0002166641680000021
5. a process for the preparation of an intermediate I according to any one of claims 1 to 3, which comprises:
ii) reaction of the intermediate I-1 with boric acid or a borate to give an intermediate I-2
Figure FDA0002166641680000022
Wherein the content of the first and second substances,
X1、X2is halogen, preferably, said X1、X2Is chlorine, bromine or iodine;
b represents boron, preferably10Boron;
R10and R20Is OH or together with the boron atom to which they are attached represents a substituent hydrolysable to a boronic acid group, preferably a boronic acid pinacol ester group;
R3and R4Hydrogen, a protecting group for amino group, or an imino group which forms a protecting group for amino group together with amino group, respectively;
R5is a protecting group for hydrogen or carboxyl.
6. The method of claim 5, wherein the method further comprises:
i) the intermediate II reacts with the intermediate III to obtain an intermediate I-1
Figure FDA0002166641680000031
Wherein the content of the first and second substances,
X1、X2、X3are each halogen; preferably, said X1、X2、X3Is chlorine, bromine or iodine;
R3and R4Each independently hydrogen or a protecting group for amino or together with amino forms an imino group for protecting amino;
R5is a protecting group for hydrogen or carboxyl.
7. The process of claim 6, wherein said intermediate III is
Figure FDA0002166641680000032
The intermediate I-1 is
Figure FDA0002166641680000033
Wherein, X1、X2Is halogen, preferably, said X1、X2Is chlorine, bromine or iodine; r5Is a protecting group for hydrogen or carboxyl.
8. The method of claim 5, wherein the method further comprises: and (3) carrying out manual resolution on the intermediate I-1, and then respectively reacting with boric acid or boric acid ester.
9. Use of the intermediate I according to any one of claims 1 to 4 for the preparation of the intermediate I18F-BPA, said18F-BPA has the structure:
Figure FDA0002166641680000034
10. use of the intermediate I according to claim 9, characterized in that it is prepared by the intermediate I18The process for F-BPA comprises:
reacting intermediate I-2 with18F ion reaction to obtain18F-substituted compounds
Figure FDA0002166641680000041
And/or deprotection of said18Protecting groups in F-substituted compounds to give18F-BPA
Figure FDA0002166641680000042
Wherein, R is10And R20Is OH or together with the boron atom to which they are attached represents a substituent hydrolysable to a boronic acid group;
R3and R4Each hydrogen, a protecting group for amino group or together with amino groupTo an imino group for protecting an amino group;
R5is a protecting group for hydrogen or carboxyl.
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